BR112016011111B1 - IMPROVED PHARMACEUTICAL COMPOSITIONS OF PIMOBENDAN - Google Patents

Abstract

IMPROVED PHARMACEUTICAL COMPOSITIONS OF PIMOBENDAN. The present invention is directed to a composition comprising pimobendan particles with an integral coating of a carrier matrix which serves to ensure a rapid dissolution of the active substance in every pH condition representing the gastrointestinal tract and therefore a reliable absorption, and a method of microencapsulating pimobendan using spray freezing technology and incorporating the coated particles into oral formulations, eg tablets.

Description

FIELD OF THE INVENTION

[0001] The invention relates to the field of medicine, in particular, to the field of veterinary medicine. The invention relates to improvements in oral formulations of the phosphodiesterase inhibitor pimobendan used for the treatment of congestive heart failure arising from valvular insufficiency or dilated cardiomyopathy, and to methods of producing the formulations.

BACKGROUND INFORMATION

[0002] Pimobendan (4,5-dihydro-6-(2-(4-methoxyphenyl)-1 H-benzimidazol-5-yl)-5-methyl-3(2H))-pyridazinone) is a benzimidazole-pyridazone derivative which has been described in EP 0 008 391 as a substance having cardiotonic, hypotensive and antithrombotic activities.

[0003] EP 0 439 030 discloses the low solubility of pimobendan in aqueous environment which is further characterized by a highly pH-dependent nature. Depending on the buffer system used, about 100 to 300 mg/liter will dissolve at a pH between 1 and 3, but at pH 5 only about 1 mg/liter will dissolve in water. In humans, this phenomenon resulted in very unstable blood concentrations so that levels were often very low. These unsatisfactory absorption characteristics were explained by the high pH dependence of pimobendan solubility in aqueous media and the unstable pH conditions in the gastrointestinal tract of the test subjects. According to this patent, the low solubility and high pH dependence of the solubility of pimobendan can be overcome by using an intimate dry mixture of pimobendan powder and citric acid powder, said mixture having about up to one part by weight of pimobendan to not less than about five parts by weight of citric acid and pharmaceutically active carriers, which is filled into capsules or compressed into tablets for oral administration. Very unstable blood concentrations are said to be prevented by the acid microsphere, which is caused by the dissolution rate of citric acid, formed around the pimobendan particles. Said microsphere is always acidic and ensures reliable and virtually pH-independent dissolution and absorption of pimobendan. WO 2005/084647 refers to an innovative solid formulation comprising pimobendan which is homogeneously dispersed in a polyvalent acid selected from the group consisting of citric acid, acetic acid, maleic acid, tartaric acid or its anhydride, and a flavoring substance. According to said publication, the high amount of citric acid and its acidic taste are not readily accepted by most animals. Therefore, these formulations need to be forcibly ingested by the animals or mixed with food prior to application. According to document WO 2005/084647, these difficulties can be overcome using this new formulation, preferably in the form of tablets. The most preferred mode is a tablet characterized in that the tablet comprises 1.25 mg, 2.5 mg, 5 mg or 10 mg of pimobendan, and further comprises citric acid, preferably, and an amount of 50 mg/g solid formulation, artificial beef flavor and pharmaceutically acceptable excipients.

[0004] WO 2010/055119 discloses an innovative formulation, comprising pimobendan and an organic carboxylic acid, in which the only organic carboxylic acid is succinic acid, and the ratio between the weight of succinic acid and pimobendan is at least 11:1.

[0005] WO 2010/010257 refers to the use of a coating composition for application in a solid veterinary pharmaceutical composition produced from pimobendan by a film coating method comprising a powder stimulating material, a binder and a solvent.

[0006] EP 2 338 493 provides new crystalline forms of pimobendan, the solubility characteristics of which are such that an organic acid or an anhydride thereof is not necessary to ensure satisfactory reabsorption of the substance.

[0007] Regarding its biopharmaceutical properties, pimobendan can be classified in Class IV in the biopharmaceutical classification systems (BSC). This means that it exhibits challenging molecular properties such as low solubility and low permeability; both of which are considered rate-limiting steps for absorption. However, the unsatisfactory absorption characteristics of pimobendan can be explained mainly by the high pH dependence of its solubility in aqueous media and by the unstable pH conditions in the gastrointestinal tracts of the target animals to be treated. It is known that even the pH of gastric juices can vary within a relatively wide range, that is, between 1 and 5, depending on the presence of food. Fasting gastric pH in dogs has been observed to vary between 0.9 and 2.5, whereas gastric pH may exhibit an elevation of 2 to 3 pH units in the first postprandial hour. In addition, intestinal juices are also characterized by unstable pH conditions in the range of 3 to 7.5.

[0008] According to the state of the art, the unsatisfactory absorption of pimobendan due to its high pH dependence of solubility is avoided by simultaneously administering large amounts of an organic acid in the formulation or using a different crystalline form (polymorphic) of the substance.

[0009] The objective underlying the present invention is, therefore, to provide an improved formulation of pimobendan, which overcomes the problems of the prior art.

SUMMARY OF THE INVENTION

[0010] Surprisingly, the inventor succeeded in overcoming the high pH dependence of the solubility of pimobendan and ensuring a very satisfactory dissolution rate in all pH conditions representing the gastrointestinal tract and therefore a satisfactory absorption even that there are considerable pH fluctuations in the gastrointestinal tract, without the use of an organic carboxylic acid or without modifying the crystalline form of the substance by applying the lipid embedding (lipid coating) approach. Pimobendan lipid-embedded particles are produced using spray freezing technology, for example as described in US 4,865,851. Spray freezing (also known as spray cooling) is one of the methods used to produce microparticles or, more specifically, microspheres. These are solid, approximately spherical particles in the micrometer range in size, in which the drug is homogeneously distributed within the entire volume of the particle. The embedded particles exhibit rapid and substantial dissolution of pimobendan from oral formulations at every pH representing the gastrointestinal tract of target animals, ensuring adequate drug absorption regardless of highly varying pH conditions. The spray-freezing technology designed to produce the lipid-embedded particles is fast, easy to scale up, and inexpensive. It is environmentally friendly as no solvent is required in the formulation and manufacturing process. With the use of the lipid-embedded particles it was possible to formulate palatable oral pimobendan formulations that dissolve rapidly and substantially in all pH conditions representing the environment(s) of the gastrointestinal tract without including any acidic compounds.

[0011] In one aspect, the object of the present invention has surprisingly been solved by providing a composition comprising pimobendan in particulate form coated with a carrier matrix, wherein the carrier matrix essentially consists of one or more pharmaceutically acceptable carriers. acceptable selected from the following groups: (a) polyglycolized glycerides, (b) polyethylene glycols (PEGs).

[0012] In another aspect, the object of the present invention has surprisingly been solved by providing a composition comprising pimobendan in particulate form coated with a carrier matrix, wherein the carrier matrix essentially consists of one or more pharmaceutically acceptable carriers. acceptable materials selected from the following groups: (a) polyglycolized glycerides, (b) polyethylene glycols (PEGs), and wherein coating with the carrier matrix serves to ensure rapid and substantial dissolution of pimobendan regardless of pH conditions.

[0013] In yet another aspect, the object of the present invention has surprisingly been solved by providing a process for preparing a composition, as disclosed herein, comprising (a) dispersing particulate pimobendan in a molten carrier matrix, ( b) atomizing the dispersion obtained in step (a), and (c) cooling and collecting the coated particles.

[0014] In yet another aspect, the object of the present invention has surprisingly been solved by providing the composition comprising pimobendan in particulate form coated with a carrier matrix obtainable by the processes for preparing a composition as disclosed herein.

[0015] In yet another aspect, the object of the present invention has surprisingly been solved by providing the pharmaceutical composition for oral administration to warm-blooded animals, preferably pets, in particular dogs, which comprises a veterinary effective amount of the composition as described herein, one or more physiologically acceptable excipients and, optionally, veterinary effective amounts of one or more additional active ingredients selected from angiotensin enzyme (ACE) inhibitors, aldosterone antagonists and/or diuretics handle.

[0016] By applying the pharmaceutical composition according to the present invention, the low solubility and the high pH dependence of the solubility of pimobendan can be overcome without simultaneously administering large amounts of organic acid or without using a crystalline form different (polymorphic) substance as demonstrated by the rapid and substantial dissolution of the active compound at each pH representing the environment(s) of the gastrointestinal tract of animals. Virtually pH-independent dissolution ensures satisfactory absorption even under unstable pH conditions of treated subjects.

DETAILED DESCRIPTION OF THE INVENTION

[0017] Before the embodiments of the present invention are described in greater detail, it should be noted that, as used herein and in the appended claims, the singular forms "a", "an", "the" and "the " include plural references unless the context clearly indicates otherwise.

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by an individual of ordinary skill in the art to which this invention pertains. All ranges and values can vary by 1 to 5% unless otherwise indicated or otherwise understood by an individual skilled in the art, therefore the term "about" has generally been omitted from the description and claims. While any methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present invention, preferred methods, devices, and materials are now described. All publications mentioned herein are incorporated herein by reference for the purpose of describing and disclosing the substances, excipients, carriers and methodologies, as reported in the publications, which may be used in connection with the invention. Nothing in this document should be construed as an admission that the invention does not have the right to title to backdate such description by virtue of a prior invention.

[0019] In one aspect, the object of the present invention has surprisingly been solved by providing the process for preparing a composition, as disclosed herein, comprising (a) dispersing particulate pimobendan, preferably with a particle size average less than 20 µm, in a molten carrier matrix, such as polyglycolized glycerides, preferably stearoyl macrogol-32 glycerides, more preferably Gelucire 50/13, and/or polyethylene glycols, preferably with an average molecular weight from 1,500 to 20,000 g/mol, more preferably with an average molecular weight from 4,000 to 6,000 g/mol, most preferably PEG 6000, wherein the carrier matrix preferably has a melting point of 40°C at 80°C, more preferably from 50°C to 70°C, using conventional dispersion techniques, for example using a high shear mixer, to yield a dispersion, preferably a homogeneous suspension; (b) atomizing the dispersion obtained in step (a) using conventional atomizers such as rotary atomizers, pressure or pneumatic nozzles and/or sonic nozzles, preferably fitted in a standard spray freezing/cooling apparatus, plus preferably using a two-fluid pneumatic or pressure nozzle atomizing system fitted in a standard spray freezing/cooling apparatus using atomizing gas pressures of 100 to 1000 KPa (1 to 10 bar) preferably 200 to 800 KPa (2 to 8 bar) and more preferably 300 to 600 KPa (3 to 6 bar); and (c) cooling and collecting the coated particles by conventional cooling and collection techniques, for example by applying a stream of cold air or an inert gas such as dry nitrogen, preferably at a temperature of 0° to 30°C, more preferably at a temperature of 3° to 15°C, even more preferably at a temperature of 5° to 15°C, most preferably at a temperature of 4° to 8°C, at sprinkling apparatus and collecting the particles, preferably in a cyclonic separator or a bag filter.

[0020] According to a further aspect, the object of the present invention has surprisingly been solved by providing a composition comprising pimobendan particles with an integral coating of a carrier matrix, wherein the carrier matrix essentially consists of one or more pharmaceutically acceptable carriers from groups of polyglycolized glycerides and polyethylene glycols, and where pimobendan exhibits, from the relevant composition or drug forms, rapid and extensive (rapid and substantial) dissolution under all conditions values that represent the environment(s) of the gastrointestinal tract of target animals.

[0021] According to a further aspect, the present invention provides pharmaceutical compositions for oral administration to pets, particularly dogs, which comprise pimobendan lipid-embedded particles in a suitable vehicle.

[0022] According to yet another aspect, the invention provides a method of ensuring a reliable rapid and substantial dissolution of pimobendan in each pH condition representing the gastrointestinal tract of target animals comprising the coating of pimobendan with a suitable carrier and incorporating the embedded particles into oral formulations, for example, in tablets.

[0023] In order to effectively overcome the high pH dependence of pimobendan solubility and provide coated particles that exhibit rapid and substantial dissolution under all pH conditions representing the gastrointestinal tract of dogs, the average diameter of coated pimobendan particles should preferably be less than 50 μm.

[0024] The melting point of the carrier should be high enough to prevent melting of the coated particles in the mouth, but not so high that the pimobendan itself melts and/or becomes chemically degraded during the coating process. Therefore, the carrier or a mixture of carriers used as the carrier matrix in the present invention will have a melting point of 40°C to 80°C and preferably 50°C to 70°C.

[0025] Suitable carriers for coating pimobendan are selected from the groups of polyglycolized glycerides and polyethylene glycols.

[0026] Polyglycolized glycerides are mixtures of fatty acid glycerides and polyoxyethylene esters with fatty acids. In these mixtures, the fatty acids are saturated or unsaturated and the glycerides are mono, di or triglycerides or mixtures thereof in any proportions. Examples of suitable polyglycolized glycerides include, but are not limited to, lauroyl macrogol glycerides or stearoyl macrogol glycerides.

[0027] In a particular group of compositions, the polyglycolized glycerides contained in the carrier matrix have a hydrophilic to lipophilic balance (HLB) value greater than 10. In additional particular groups of compositions, the polyglycolized glycerides contained in the carrier matrix carrier are dispersible in water. In a further particular group of compositions, the polyglycolized glycerides are stearoyl macrogol glycerides. In yet another particular group of compositions, the polyglycolized glyceride is stearoyl macrogol-32 glycerides (eg, Gelucire 50/13). Macrogol-32 stearoyl glycerides are semi-solid-solid at room temperature with a melting point of 50°C.

[0028] USP polyethylene glycols (PEGs), alternatively known as macrogols, are hydrophilic polymers of oxyethylene. PEGs having an average molecular weight greater than 900 g/mol are generally semi-solids or solids at room temperature. A suitable average molecular weight range for the PEGs in the present invention is 1,500 to 20,000 g/mol. Suitable commercially available products include, but are not limited to, PEG 1500, PEG 4000 and PEG 6000. In a particular group of compositions, the PEG(s) present in the carrier matrix have an average molecular weight range between 4000 and 6000 g /mol. In an additional particular group of formulations of this embodiment, this PEG has an average molecular weight of about 6000 g/mol.

[0029] According to an embodiment of the present invention, the carrier matrix used for coating pimobendan consists of one or more pharmaceutically acceptable carriers selected from the groups of polyglycolized glycerides and polyethylene glycols.

[0030] In a further embodiment of the invention, the carrier matrix is a polyglycolized glyceride. Suitably, the polyglycolized glyceride is lauroyl macrogol glycerides or stearoyl macrogol glycerides, particularly stearoyl macrogol-32 glycerides.

[0031] In yet another further embodiment of the invention, the carrier matrix is a polyethylene glycol, particularly PEG 6000.

[0032] In a further embodiment of the invention, the carrier matrix comprises a mixture of the polyglycolyzed menum glyceride and the polyethylene glycol menum. Suitably, the polyglycolized glyceride present in this embodiment is stearoyl macrogol-32 glycerides, and suitably the stearoyl macrogol-32 glycerides are present in an amount to make up 10 to 100% by weight of the carrier matrix component of the composition, and preferably represent 20 to 50% by weight of the carrier matrix component of the composition. Conveniently, the polyethylene glycol present in this embodiment has an average molecular weight between 4,000 and 6,000 g/mol and, suitably, the PEG is present in an amount to make up 10 to 100% by weight of the matrix component. composition carrier, and preferably 30 to 80% by weight of the composition carrier matrix component. Preferably, there is only a polyglycolized glyceride and a polyethylene glycol present in such an embodiment.

[0033] In a particular group of formulations of this embodiment, this polyglycolized glyceride belongs to the stearoyl macrogol-32 glycerides, and the PEG has an average molecular weight of 6,000 g/mol. Preferably, the stearoyl macrogol-32 glycerides and polyethylene glycol 6000 are present, independently of one another, in amounts to make up 10% by weight to 100% by weight of the carrier matrix component of the composition, preferably 20% by weight to 75% by weight of the carrier matrix component of the composition, more preferably, 20% by weight to 50% by weight of the carrier matrix component of the composition.

[0034] The lipid-coated particles according to the invention will contain 1 to 80%, preferably 5 to 30%, most preferably 10 to 20% pimobendan on a weight for weight (w/w) basis.

[0035] The lipid-coated particles of the invention are characterized by an average value (D50) of particle size distribution, generally less than 500 μm, preferably less than 300 μm, more preferably less than 250 μm and, even more preferably, less than 200 µm. Particle size control is necessary to ensure that dissolution of pimobendan from the subsequently formulated product will be rapid and substantial under all pH conditions representing the gastrointestinal tract of the target animals. Coated particles that have a D50 value of less than 200 µm are preferred in this regard. The D50 value represents the average particle size in a given particle size distribution, that is, the particle size value of which 50% of all particles are smaller. For example, a D50 value of 200 μm means that 50% of all particles have a particle size less than 200 μm.

[0036] The lipid-coated particles of the invention can be prepared by atomizing a dispersion of pimobendan in a molten carrier matrix and cooling the particles thus obtained, and such a process constitutes a further feature of the invention. The dispersion can be prepared by adding particulate pimobendan to the carrier or molten carrier mixture or, alternatively, by mixing the dispersion ingredients together in the solid state and melting the carrier matrix. The particulate pimobendan can be dispersed into the molten carrier matrix using conventional techniques, for example using a high shear mixer. In general, the temperature of the molten carrier matrix should be 20 to 40°C above its melting point. In general, the carrier or carrier mixture used for coating pimobendan particles should have a melting point within the range of 40 to 80°C, preferably 50 to 70°C, and the matrix temperature of fused carrier will be 20 to 40°C above its melting point. Atomization techniques that can be applied include the use of conventional atomizers such as spinning atomizers, pressure nozzles and sonic nozzles. The use of a two-fluid nozzle atomizer fitted to a standard spray freeze/cooler is particularly convenient.

[0037] In the atomization process, the molten dispersion will generally be supplied to the atomizer head at a temperature in the range of 70°C to 100°C, preferably 75°C to 95°C, more preferably 75°C to 90°C, the precise temperature depending on the specific carrier matrix used. The atomizing gas supplied to the nozzle can be air or an inert gas such as nitrogen. The pressure of the atomizing gas is between 100 and 1000 KPa (1 and 10 bar), preferably between 200 and 800 KPa (2 and 8 bar) and most preferably between 300 and 600 KPa (3 and 6 bar). The atomization pressure is desirably controlled in order to produce particles of the preferred size.

[0038] The coated particles can be solidified and collected by conventional techniques. The coated particles can conveniently be solidified by applying a stream of cold air or dry nitrogen to the spray chamber at a temperature between 0°C and 30°C, preferably 3°C and 15°C, more preferably 5°C and 15°C, most preferably 4°C and 8°C. The lipid-coated particles are collected as a free-flowing powder using either a cyclonic separator or a bag filter. The coated particles are spherical in shape and have a D50 value of less than 500 µm, preferably less than 300 µm, more preferably less than 250 µm, and even more preferably less than 200 µm.

[0039] The lipid-coated particles of the invention can be incorporated into a pharmaceutical composition for oral administration, with the use of pharmacologically active ingredients and/or physiologically acceptable carriers and/or additional excipients.

[0040] Compositions according to the invention may, for example, include tablets, granules, powders, suspensions, oral pastes and gels. Tablets including chewable tablets represent the particularly preferred dosage form.

[0041] Accordingly, the present invention relates, in one embodiment, to an oral pimobendan formulation, preferably a tablet, comprising - a veterinary effective amount of pimobendan as the active substance in lipid-coated particulate form, and - physiologically acceptable excipients.

[0042] The amount of pimobendan in the oral formulations is preferably in the range of 0.01% to 10% by weight, more preferably 0.5% to 1.0% by weight, based on the whole formulation.

[0043] The oral pimobendan formulations of the present invention may also comprise veterinary effective amounts of additional active ingredients which may be selected from angiotensin converting enzyme (ACE) inhibitors, aldosterone antagonists and/or loop diuretics. Non-limiting examples of actives that can be used in combination with the lipid-coated pimobendan particles according to the invention are: benazepril (in CAS 86541-75-5), spironolactone (in CAS 52-01-7) and/or furosemide (in CAS 54-31-9), all, and independently of one another, in free form or in the form of a physiologically acceptable salt which is preferably embedded in a carrier (lipid) matrix. That is, additional active substances can also be added to oral pimobendan formulations in the form of lipid-embedded particles, produced by using the spray-freezing technique, i.e. particles coated with a (lipid) carrier matrix. . Preferably, the oral pimobendan formulations of the present invention also comprise veterinary effective amounts of benazepril, in free form or in the form of a physiologically acceptable salt, which is preferably embedded in a carrier matrix. Additional active substances may be present in the oral formulations of the invention in the range of 0.01 to 50% by weight, preferably 0.1 to 20% by weight, based on the total weight of the formulation/composition.

[0044] Oral pimobendan compositions can be formulated using conventional pharmaceutically acceptable excipients. Therefore, for example, tablets can be prepared using binding agents (e.g. pregelatinized starch, polyvinyl pyrrolidine or hydroxypropyl methyl cellulose), fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate), lubricants (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate). for example magnesium stearate, talc or colloidal silica), disintegrants (for example starch or sodium starch glycoate) or wetting agents (for example sodium lauryl sulfate). The tablet formulations of the present invention additionally contain one or more physiologically acceptable natural or synthetic flavorings. Preferred flavoring agents are artificial beef flavor, liver powder and fermenting yeast. Flavoring agents are preferably present in the tablet formulations of the invention in the range of 1.0% by weight to 60% by weight, more preferably, from 5.0% by weight to 30% by weight, based on weight. total formulation/composition.

[0045] The oral paste or gel formulation of the present invention may contain pharmaceutically acceptable excipients, for example thickeners (for example, xanthan gum, polyvinylpyrrolidones, polyacrylates such as carbopols, corn starch, microcrystalline cellulose, hydroxyethyl cellulose, carbon dioxide silicon or combinations thereof), humectants (e.g. glycerol), preservatives (e.g. benzyl alcohol, benzoic acid, benzoates or p-hydroxybenzoates, pH adjusting agents (bases or acids), binders, fillers, active agents or surface dispersion. Said pharmaceutically acceptable excipients are known to those skilled in the art of veterinary formulation technology. The oral paste and gel formulations of the present invention also contain veterinally acceptable flavoring agents. Suitable flavoring agents within the compositions of the invention are, for example, artificial beef flavor, food extracts, such as dissected liver or malt extract and honey flavors.

[0046] The pharmaceutical compositions of the invention can be prepared according to conventional techniques well known in the pharmaceutical industry. Therefore, for example, tablets can be prepared by direct compression of a dry mixture of the lipid-coated pimobendan particles with excipients and, optionally, with additional active substances by wet granulation. Oral paste or gel formulations can be obtained by dispersing the lipid-coated particles of pimobendan and, optionally, the additional active ingredients in suitable vehicles.

[0047] Compositions for use in accordance with the present invention may, if desired, be presented in a pack or dispensing device which may contain one or more unit doses. The pack may, for example, comprise metal or plastic foil, such as a blister pack.

[0048] The formulations of the present invention are suitable for the treatment of congestive heart failure arising from valvular insufficiency or dilated cardiomyopathy in pets, in particular in dogs.

[0049] Efficacy is based on a satisfactory dissolution and subsequent absorption of the active substance. The dissolution profiles of the tablet formulation according to the present invention and those of commercially available tablets, both containing 5 mg of pimobendan, were compared in buffers of pH 1.2, 4.5 and 7.5, i.e. , under pH conditions representing different parts/environments of the gastrointestinal tract of pets. Dissolved concentrations of pimobendan were determined by a validated UHPLC method.

[0050] The oral formulations according to the present invention exhibit a high palatability, which means the voluntary acceptance or ingestion of the formulations by warm-blooded animals, for example, pets, in particular by dogs. Acceptability of oral formulations containing lipid-coated pimobendan particles and suitable additional ingredients according to the present invention was tested in dogs.

BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1: Comparative dissolution profiles of tablet formulations containing 5 mg of pimobendan prepared according to Example 3 of the invention and commercially available as chewable tablets, respectively, in a highly acidic pH region (pH 1.2) . Test conditions: V=1000 ml, rotation speed=100 rpm, chromatographic conditions: Agilent Infinity 1290 UHPLC, RP18, 50x3.0 mm, 1.7 μm column, 27:73 v/v% acetonitrile: phosphate buffer as the mobile phase, 0.4 ml/min flow rate, detection wavelength 290 nm.

[0052] Figure 2: Comparative dissolution profiles of tablet formulations containing 5 mg of pimobendan prepared according to Example 3 of the invention and commercially available as chewable tablets, respectively, in the moderately acidic pH region (pH 4.5) . Test conditions are the same as in Figure 1.

[0053] Figure 3: Comparative dissolution profiles of tablet formulations containing 5 mg of pimobendan prepared according to Example 3 of the invention and commercially available as chewable tablets, respectively, in the neutral acid pH region (pH 7.5) . Test conditions are the same as in Figure 1.

EXAMPLES

[0054] The following examples serve to further illustrate the present invention; however, they should not be interpreted as a limitation of the scope of the invention disclosed in this document.

EXAMPLE 1 - LIPID COATING OF PIMOBENDAN

[0055] Gelucire 50/13 (18.0 kg) was melted in a stainless steel vessel and the temperature raised to 85°C. Pimob endan (2.0 kg) with an average particle size < 20 µm was added to the molten lipid. The molten dispersion was mixed with a high shear mixer to yield a homogeneous suspension and pumped into a spray freezing apparatus. The mixture was atomized using a two-fluid nozzle atomization system at atomizing gas pressures of 300 to 600 KPa (3 to 6 bar). The atomized droplets were cooled using air fed into the spray chamber at a temperature of 5 to 10°C and the solid particles were collected in a cyclone separator. The lipid-coated pimobendan comprised spherical particles with an average particle size of 90 µm.

EXAMPLE 2 - LIPID COATING OF PIMOBENDAN

[0056] Gelucire 50/13 (4.5 kg) and PEG 6000 (13.5 kg) were melted in a stainless steel vessel while increasing the temperature to 90°C. Thereto was added pimobendan (2 kg) with a particle size of < 20 µm. The molten dispersion was subjected to high shear mixing to obtain a homogeneous suspension and this mixture was spray cooled as described in Example 1 to yield a lipid-coated product that has a similar particle size and shape. For example, three different batches were produced with D50 values of 118 µm, 136 µm and 166 µm, respectively.

EXAMPLE 3 - PILL FORMULATION

[0057] Pimobendan embedded in a carrier matrix comprising Gelucire 50/13 and PEG 6000 was blended with pork liver flavor, yeast powder and additional excipients in a rotary beater. The resulting mixture was compressed into tablets using a suitable tablet press and suitable punches.

EXAMPLE 4 - PILL FORMULATION

[0058] The pimobendan coated with Gelucire 50/13, furosemide and the excipients were blended in a rotary mixer, and then the blend was compressed into tablets using a suitable tablet press and suitable punches.

EXAMPLE 5 - PILL FORMULATION

[0059] The lipid-embedded particles of pimobendan prepared according to Example 2 were blended with lipid-coated benazepril, the particles of which were embedded in a carrier matrix comprising glycerol distearate, yeast powder, lemongrass flavor. synthetic liver and additional excipients, in a rotary beater and then the resulting mixture was compacted into tablets using a suitable tablet press.

EXAMPLE 6 - IN VITRO DISSOLUTION

[0060] The absorption of pimobendan is highly dependent on the rate of dissolution of the active substance under varying pH conditions representing the gastrointestinal tract. Pimobendan dissolution profiles of tablets prepared according to Example 3 of the present invention and commercially available chewable tablets, both containing 5 mg of active substance, were compared under different pH conditions representing the gastrointestinal tract. The results are shown in Figures 1 to 3. As can be seen from these data, the dissolution rate of pimobendan from the tablet formulation prepared in accordance with the present invention was rapid and substantial at every pH tested. At pH 1.2, the speed and rate of dissolution of the formulation according to the present invention and commercially available chewable tablets were practically the same. However, at pH 4.5 and 7.5, the dissolution of the active substance was faster and more extensive of the tablet formulation according to the invention than that of the reference product. These results clearly demonstrate that the tablet formulation prepared according to the invention ensures a very satisfactory dissolution of pimobendan in all conditions representing the gastrointestinal tract, even if there are considerable pH fluctuations in it, without comprising any organic carboxylic acid, which it is present in large amounts in the commercially available product.

EXAMPLE 7 - IN VITRO DISSOLUTION

Pimo=pimobendan; Bena=benazepril

Pimo=pimobendan; Bena=benazepril

Pimo=pimobendan; Bena=benazepril[0061] The dissolution profiles of pimobendan and benazepril from tablets prepared according to Example 5 and containing 2.5 mg of pimobendan and 5 mg of benazepril were compared with commercially available chewable tablet formulations in pH 1 buffers, 2, 4.5 and 7.5. The results obtained from the present study demonstrate that the dissolution of pimobendan and benazepril from formulation containing both active substances in lipid-embedded form is slower than in corresponding commercial formulations which only contain one active substance, i.e. for both pimobendan and benazepril, the dissolution rate of both active compounds within 45 minutes of dissolution is higher from the combination than from the commercial monoformulations in each pH condition that represents the gastrointestinal tract of dogs.

Pimo=pimobendan; Bena=benazepril

Pimo=pimobendan; Bena=benazepril

Pimo=pimobendan; Bena=benazepril

EXAMPLE 8 - PALATABILITY (ACCEPTANCE) TEST

[0062] 30 male and female dogs of different breeds and ages were tested in a shelter environment. The test subject offered each dog a single daily dose of the tablet formulation, prepared according to Example 3 of the invention, which was adapted for the animal's body weight, for 3 days. In the case of tablet formulations of the present invention, in a first instance, the tablet was offered by hand for 30 seconds. If the dog did not take the formulation, it was offered to the dog in its empty bowl. Again, the dog would have 30 seconds to take the formulation. If one of the offers mentioned above resulted in the dog voluntarily taking the tablet, this would be assessed as voluntary acceptance or taking of the tablet. If the dog spit out the tablet, it would be reported as non-acceptance. A voluntary intake was observed in 82 out of 90 possible opportunities (ie, when offered to 30 animals for 3 days). This compares to an acceptance rate of 91.1%. REFERENCES 1. Document EP 0 008 391 2. Document EP 0 439 030 3. Document EP 2 338 493 4. Document WO 2005/084647 5. Document WO 2010/010257 6. Document WO 2010/055119

Claims (13)

1. Composition, characterized in that it comprises pimobendan in particulate form coated with a carrier matrix, wherein the carrier matrix consists of pharmaceutically acceptable carrier(s) selected from the following groups: ( i) polyglycolized glycerides selected from lauroyl macrogol glycerides and/or stearoyl macrogol glycerides, (ii) a mixture of polyglycolized glycerides selected from lauroyl macrogol glycerides and/or stearoyl macrogol glycerides and polyethylene glycol(ols) (PEG). 2. Composition according to claim 1, characterized in that the carrier matrix comprises both of the following: stearoyl macrogol-32 glycerides and polyethylene glycol 6000; and preferably is a mixture of stearoyl macrogol-32 glycerides and polyethylene glycol 6000. 3. Composition according to claim 2, characterized in that the stearoyl macrogol-32 glycerides and polyethylene glycol 6000 are present, independently of each other, in amounts to compose 10% by weight to 100% by weight of the carrier matrix component of the composition, preferably 20% by weight to 75% by weight of the matrix component of the composition carrier, more preferably 20% by weight to 50% by weight of the matrix component of the composition carrier. 4. Composition, according to any one of claims 1 to 3, characterized in that it consists of

5. Composition according to any one of claims 1 to 4, characterized in that the mean particle size distribution value (D50 value) of the coated particles, i.e. pimobendan in particulate form coated with a matrix of carrier, is less than 500 μm, preferably less than 300 μm, more preferably less than 250 μm, and even more preferably less than 200 μm; and wherein, preferably, the coated particles are spherical in shape. 6. Composition according to any one of claims 1 to 5, characterized in that the pimobendan content of the coated particles is in the range of 1% by weight to 80% by weight, preferably from 5% by weight to 30% by weight, more preferably from 10% by weight to 20% by weight. 7. Process for preparing a composition, as defined in any one of claims 1 to 6, characterized in that it comprises (a) dispersing particulate pimobendan in a molten carrier matrix, (b) atomizing the dispersion obtained in step ( a), and (c) cooling and collecting the coated particles. 8. Process for preparing a composition, according to claim 7, characterized in that it comprises (a) dispersing particulate pimobendan, preferably with an average particle size of less than 20 μm, in a molten carrier matrix , such as (i) polyglycolized glycerides, preferably stearoyl macrogol-32 glycerides, more preferably Gelucire 50/13, or (ii) polyglycolized glycerides, preferably stearoyl macrogol-32 glycerides, more preferably Gelucire 50/13, and polyethylene glycols, preferably with an average molecular weight of 1,500 to 20,000 g/mol, more preferably, with an average molecular weight of 4,000 to 6,000 g/mol, most preferably PEG 6000, where the carrier matrix has, of preferably a melting point of 40°C to 80°C, more preferably 50°C to 70°C, using conventional dispersion techniques, for example using a high shear mixer, to yield a dispersion, preferably a, a homogeneous suspension; (b) atomizing the dispersion obtained in step (a) using conventional atomizers such as rotary atomizers, pressure or pneumatic nozzles and/or sonic nozzles, preferably fitted in a standard spray freezing/cooling apparatus, plus preferably using a two-fluid pneumatic or pressure nozzle atomizing system fitted in a standard spray freezing/cooling apparatus using atomizing gas pressures of 100 to 1000 KPa (1 to 10 bar) preferably 200 to 800 KPa (2 to 8 bar) and more preferably 300 to 600 KPa (3 to 6 bar); and (c) cooling and collecting the coated particles by conventional cooling and collection techniques, for example by applying a stream of cold air or an inert gas such as dry nitrogen, preferably at a temperature of 0° to 30°C, more preferably at a temperature of 3° to 15°C, even more preferably at a temperature of 5° to 15°C, most preferably at a temperature of 4° to 8°C, to the apparatus of aspersion and collecting the particles, preferably, in a cyclonic separator or a bag filter. 9. Pharmaceutical composition, characterized in that it is for oral administration to warm-blooded animals, preferably pets, in particular dogs, comprising a veterinary effective amount of the composition, as defined in any one of claims 1 to 6, physiologically acceptable excipient(s) and, optionally, veterinary effective amounts of benazepril. 10. Pharmaceutical composition according to claim 9, characterized in that benazepril, and/or derivatives thereof, is in free form or in the form of a physiologically acceptable salt, which is preferably embedded in a carrier matrix. 11. Pharmaceutical composition, according to claim 9 or 10, characterized in that it is in the form of tablets. 12. Pharmaceutical composition according to any one of claims 9 to 11, characterized in that it comprises pimobendan in the range of 0.01% by weight to 10% by weight based on the weight of the entire pharmaceutical composition, preferably from 0.5% by weight to 1.0% by weight based on the weight of the entire pharmaceutical composition. 13. Pharmaceutical composition according to any one of claims 9 to 12, characterized in that benazepril is present in the composition in the range of 0.01% by weight to 50% by weight based on the weight of the entire pharmaceutical composition preferably from 0.1% by weight to 20% by weight based on the weight of the entire pharmaceutical composition.

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